EP0097874B1 - Process for the preparation of 6-exo-alkanoyl-1,3,3-trimethyl-bicyclo(2.2.2.)octan-2-ones - Google Patents

Description

The invention relates to a new process of 6-exo-alkanoyl-1,3,3-trimethyl-bicyclo [2.2.2] octan-2-one by reacting 2,6,6-trimethyl-cyclohexa-2,4-diene -1-one (11) with ethynyl alkyl ketones and catalytic hydrogenation of the Diels-Alder adduct obtained.

The process products are important intermediates for the synthesis of patchouli alcohol, which is highly sought after as a fragrance component, and its derivatives of the formula

There has been no shortage of attempts to find a particularly advantageous synthesis for these ketones.

umgesetzt wird, welche durch Hydrieren und Equilibrieren in die gewünschten Verbindungen der Formel I überführt werden können. Da bei dieser Equilibrierung lediglich exo/endo Gemische anfallen, muß bei den in der Literatur beschriebenen Verfahren auf der letzten Stufe unvorteilhafterweise eine fraktionierte Kristallisation oder eine chromatographische Epimerentrennung vorgenommen werden. Diese Operationen dürften die Wirtschaftlichkeit des beschriebenen Verfahrens beträchtlich einschränken.So from the European patent application 00 31 965 and from Chem. Commun. 1968, p. 1287 Process for the preparation of the bicyclic ketones of the formula known in which the 2,6,6-trimethyl-cyclohexa-2,4-dien-1-one of the formula 11 with alkyl vinyl ketones to the endo-configured bicycles of the general Formula V

is implemented, which can be converted into the desired compounds of formula I by hydrogenation and equilibration. Since only exo / endo mixtures are obtained in this equilibration, the processes described in the literature disadvantageously require a fractional crystallization or a chromatographic epimer separation on the last stage. These operations are likely to limit the economics of the described method considerably.

It was more specifically the object of the invention to find a process for the preparation of the bicyclic ketones of the general formula in which the last disadvantageous reaction step is not necessary.

It has now surprisingly been found that a bicyclic diene of the formula IV is formed in the reaction of 11 with ethynylalkyl ketones, in the catalytic hydrogenation of which by exclusive α attack by the hydrogen the exo isomers required for the synthesis of patchouli alcohol are isomerically pure and in better Yield than is obtained with the methods known from the literature.

in der R für Wasserstoff oder einen gesättigten, verzweigten oder unverzweigten, aliphatischen Kohlenwasserstoffrest mit 1 bis 6 C-Atomen steht, das dadurch gekennzeichnet ist, daß man

• A. 2,6,6-Trimethyl-cyclohexa-2,4-dien-1-on der Formel II
  
  mit einem Ethinylketon der allgemeinen Formel 111
  
  in der R die oben angegebene Bedeutung hat, gegebenenfalls in einem inerten Lösungsmittel auf Temperaturen von 100 bis 200, vorzugsweise 100 bis 150°C erhitzt und
• B. das erhaltene ungesättigte bicyclische Keton der allgemeinen Formel IV
  
  in Gegenwart von Edelmetallkatalysatoren katalytisch hydriert.

The invention accordingly relates to a process for the preparation of 6-exo-alkanoyl-1,3,3-trimethyl-bicyclo [2.2.2] octan-2-ones of the general formula

in which R represents hydrogen or a saturated, branched or unbranched, aliphatic hydrocarbon radical having 1 to 6 carbon atoms, which is characterized in that

• A. 2,6,6-trimethyl-cyclohexa-2,4-dien-1-one of the formula II
  
  with an ethynyl ketone of the general formula III
  
  in which R has the meaning given above, optionally heated in an inert solvent to temperatures of 100 to 200, preferably 100 to 150 ° C. and
• B. the obtained unsaturated bicyclic ketone of the general formula IV
  
  catalytically hydrogenated in the presence of noble metal catalysts.

The process according to the invention is thus shorter by the last and most critical reaction stage.

The ethynyl alkyl ketones required for the process according to the invention can be prepared in a simple manner by ethynylating aliphatic aldehydes and oxidizing the resulting alcohols. Compared to the vinyl alkyl ketones used as starting compounds in the known process, they are distinguished by a significantly lower sensitivity to polymerization.

11 is advantageously used in the form of its dimer, since this is the only form that is stable in storage and splits into the monomers anyway at higher temperatures.

To react 11 with the ketones of the formula 111 to the bicyclooctadiene dions of the formula IV, the components are simply heated together or in an inert, higher-boiling solvent. At least equimolar amounts, preferably 1 to 1.2 moles, of ketone 111 are added per mole 11.

Above all, a solvent is not necessary if the reaction components are heated to the reaction temperature in the autoclave under autogenous pressure. However, it is also possible to work in an inert solvent customary for Diels-Alder syntheses, such as benzene, toluene, xylene or 1,4-dioxane. The solvent is then used in approximately the same to approximately twice the amount by weight.

wurden bei Verbindungen, in denen R eine Methylgruppe bedeutet, die 5-Isomeren nicht isoliert. Mit steigendem induktiven Effekt (bzw. steigender sterischer Hinderung) des Substituenten R nimmt der Anteil an dem unerwünschten 5-Isomeren zu. Das Verhältnis der Konstitutionsisomeren ist außerdem in gewissem Maße von der Wahl des Lösungsmittels abhängig. Dieser Effekt, der in diesem Fall zugunsten des gewünschten Verfahrensproduktes genutzt werden kann, ist überraschend, da pericyclische Reaktionen normalerweise nicht lösungsmittelabhängig sind.Of the possible constitutional isomers IV and its 5-isomer VI in this Diels-Alder reaction

the 5-isomers were not isolated for compounds in which R represents a methyl group. With increasing inductive effect (or increasing steric hindrance) of the substituent R, the proportion of the undesired 5-isomer increases. The ratio of the constitutional isomers also depends to a certain extent on the choice of solvent. This effect, which in this case can be used in favor of the desired process product, is surprising since pericyclic reactions are normally not solvent-dependent.

So z. B. when using the slightly more polar 1,4-dioxane instead of the apolar aprotic hydrocarbons, the isomer ratio shifted significantly to the side of the desired constitutional isomers.

For R = hexyl, for example, the ratio of IV: VI when working in toluene = 87.5 _: 12.5, in contrast, in 1.4-dioxane 94.3: 5.7. The situation is analogous for compounds with R = isopropyl. They amount to

The course of the implementation can be followed using the usual analytical methods. The reaction time required for the quantitative conversion of 11 is generally about 3 hours.

The reaction mixture is worked up by distilling off the solvent. The remaining residue can either be purified by distillation or - in the case of crystalline reaction products - by dissolving in hot petroleum ether, filtering and then crystallizing. The bicyclic octadienones IV crystallize out of the solution in pure form.

The catalytic hydrogenation of the bicyclooctadiendione IV is advantageously carried out in polar protic solvents such as methanol, ethanol or isopropanol, in particular in methanol. When using normal pressure up to pressures of about 30 bar and temperatures of about 100 ° C., the bicyclooctadiendiones IV react smoothly to the bicyclooctane dions of the formula 1 when using noble metal catalysts, such as Pd or Pt catalysts. Interestingly, however, a selective one succeeds in ethyl acetate as solvent Hydrogenation of the double bond in the 7-position.

With the aid of the process according to the invention, the bicyclic ketones of the general formula 1 which are of interest as important intermediates for the synthesis of the patchouli alcohol and its derivatives, which are very popular as fragrance components, are obtained in a simple manner and with better yields than by the known processes.

example 1 6-acetyl-1,3,3-trimethyl-bicyclo [2.2.2] octan-2-one

A. With stirring to the boiling solution of 95.2 g (0.7 mol) of dimeric 2,6,6-trimethyl-cyclohexa-2,4-dien-1-one (11) in 300 ml of xylene, 53 g ( 0.77 mol) of butinone was added dropwise. After the addition had ended, the mixture was heated to boiling with stirring and under reflux for 3 h.

The xylene was then distilled off, the reaction product was taken up in 0.5 l of petroleum ether and heated to boiling. The hot petroleum ether solution was filtered. 97 g (0.48 mol) of 6-acetyl-1,3,3-trimethyl-bicyclo [2.2.2j-octan-5,7-dien-2-one (IVa) crystallized from the cooled solution in the form of colorless prisms of Fixed point F. 70 to 72 ° C. This corresponds to a yield of 69% of theory.

Ba. 28 g of the 6-acetyl-1,3,3-trimethyl-bicyclo- [2.2.2] octa-5; 7-dien-2-one obtained were dissolved in 150 ml of isopropanol, the solution with 1 g of Pd / C ( 5%) and hydrogenated at 100 ° C and 30 bar for 5 h in an autoclave. The catalyst was then filtered off and the reaction product was freed from the solvent. There remained 27 g (95%) of 6-exo-acetyl-1,3,3-trimethyl-bicyclo [2.2.2] octan-2-one (la) as a colorless, slowly crystallizing oil with a melting point of F = 45 to 48 ° C.

Bb. 5 g IVa were dehydrated with 0.1 g Pt / C (5%) under otherwise the same conditions as in Ba). 5 g of la were obtained.

Bc. 5 g of IVa were dissolved in methanol, 0.1 g of Pd / C (5%) was added and the mixture was hydrogenated in an autoclave at 100 ° C. and 30 bar. 5 g of la were obtained.

Vol. 5 g of IVa were dissolved in methanol and 0.1 g of Pt / C (5%) was added. After hydrogenation at 100 ° C. and 30 bar, 5 g of la remained.

Example 2 6-exo-isobutyryl-1,3,3-trimethyl-bicyclo [2.2.2] octan-2-one

Aa. To the boiling solution of 27.2 g (0.2 mol) of the dimeric 2,6,6-trimethyl-cyclohexa-2,4-dien-1-one (11) in 100 ml of xylene was added 21.2 g with stirring (0.22 mol) of ethynyl isopropyl ketone was added dropwise. After the addition had ended, the mixture was heated to boiling with stirring and under reflux for 3 h. The xylene was then distilled off. Kugelrohr distillation (bp = 81 to 100 ° C / 0.005 mbar) of the residue gave 41.5 g of a mixture of 6-isobutyryl-1,3,3-trimethyl-bicyclo [2.2.2] octa-5,7-diene -2-ons (IVb) and his 5- Isobutyryl isomers in a ratio of 9: 2.

The isomers can be separated by crystallization from petroleum ether. The desired 6-isobutyryl derivative is obtained in the form of white crystals with a melting point of F = 60 to 63 ° C.

If dioxane was used as the solvent instead of xylene and the reaction time was extended to 5 h, a mixture of 88% IVb and 12% of the constitutionally isomeric 5-isobutyryl derivative was obtained in virtually quantitative yield under otherwise identical reaction conditions.

Ac. If methanol was used as the solvent instead of xylene and the reaction mixture was heated in an autoclave at 140 ° C. for 3 hours, a mixture of 91% IVb and 9% of the constitutionally isomeric 5-isobutyryl derivative was obtained in about 83% yield with customary workup.

Ad. A mixture of 27.2 g of 11 and 21.1 g of ethynyl isopropyl ketone was heated to 130 ° C. in an autoclave for 3 hours. A mixture of IVb and its 5-isobutyryl isomer in a ratio of 88:12 was obtained in practically quantitative yield.

B. 10 g of IVb were dissolved in 100 ml of methanol, 0.1 g of Pd / C (5%) was added and the mixture was hydrogenated at 30 bar and 100 ° C. for 3 h. Filtration, distillation of the methanol and distillation in a bulb tube gave 7.2 g of 6-exo-isobutyryl-1,3,3-trimethyl-bicyclo [2.2.2] octan-2-one as a colorless oil with a boiling point of Kp = 120 ° C / 0.01 mbar.

Example 3 6-exo- (2'-methyl-butyryl) -1,3,3-trimethyl-bicyclo [2.2.2] octan-2-one

A. Analogously to Example 2 Aa, 27.2 g of dimeric 11 were reacted with 24.2 g of 4-methyl-hex-1-in-3-one in xylene. Distillation of the reaction product gave a mixture with a boiling point Kp = 103 to 108 ° C / 0.01 mbar, which was 4 parts from 6-exo- (2'-methyl-butyryl) -1,3,3-trimethyl-bicyclo [2.2 .2] octa-5,7-dien-1-one (IVc) and 1 part consisted of the corresponding 5-isomer. The products are mixtures of diastereomers with respect to the chirality center in the side chain.

B. 10 g of the mixture obtained according to FIG. 3A were hydrogenated analogously to Example 2B. By Kugelrohr distillation of the reaction product, 7.8 g of a mixture essentially containing 6-exo- (2'-methyl-butyryl) -1,3,3-trimethyl-bicyclo [2.2.2] octan-2-one was obtained yellow oil with a boiling point of Kp = 150 to 160 ° C / 0.3 mbar.

Example 4 6-exo-propionyl-1,3,3-trimethyl-bicyclo [2.2.2] octan-2-one

A. Analogously to Example 1A, 37.3 g of dimeric 11 were reacted with 25 g of ethynyl ethyl ketone in 200 ml of xylene. Distillation of the reaction product obtained gave 49 g of a mixture of 6-propionyl-1,3,3-trimethyl-bicyclo [2.2.2] octa-5,7-dien-2-one (IVd) and its 5-propionyl isomer in Ratio 7: 1.

B. 10 g of the product obtained according to A were hydrogenated analogously to Example 2B. After Kugelrohr distillation, 7.8 g of a mixture essentially containing 6-exo-propionyl-1,3,3-trimethyl-bicyclo [2.2.2] octan-2-one remained as a colorless oil with a boiling point of 120 ° to 125 ° C./ 0.005 mbar.

Example 5 6-exo-heptanoyl-1,3,3-trimethyl-bicyclo [2.2.2] octan-2-one

Aa. Analogously to Example 1A, 27.2 g of the dimeric II were reacted with 30.4 g of ethynylhexyl ketone in 200 ml of xylene. Kugelrohr distillation of the reaction product gave 47 g of a 7: 1 mixture of 6-heptanoyl-1,3,3-trimethyl-bicyclo [2.2.2] octa-5,7-dien-2-one (IVe) and its 5- Heptanoyl isomers.

Ab. If 200 ml of 1,4-dioxane was used as the solvent instead of xylene, a mixture consisting of 94.3% IVe and 5.7% of its 5-heptanoyl isomer was obtained under otherwise identical reaction conditions. The yield was 76% of theory.

B. 10 g of the mixture obtained according to Example 5Ab were hydrogenated analogously to Example 2B. 8.7 g were obtained an essentially 6-exo-heptanoyl-1,3,3-trimethyl-bicyclo [2.2.2] octan-2-one containing mixture as a yellow oil with boiling range Kp = 120 to 150 ° C / 0.05 mbar.

Claims (1)

1. A process for the preparation of a 6-exo-alkanoyl-1,3,3-trimethyl-bicyclo[2,2,2]octan-2-one of the general formula I

   

   where R is hydrogen or a saturated, branched or linear aliphatic hydrocarbon radical of 1 to 6 carbon atoms, wherein

   A. 2,6,6-trimethyl-cyclohexa-2,4-dien-1-one of the formula II

   

   is heated together with an ethynyl ketone of the general formula III

   

   where R has the above meanings, in the presence or absence of an inert solvent, to a temperature of from 100 to 200°C, and

   B. the resulting unsaturated bicyclic ketone of the general formula IV

   

   is catalytically hydrogenated in the presence of a noble metal catalyst.